Atorvastatin is a reductase inhibitor of the enzyme 3-hydroxy-3-methylglutarate-coenzyme A (HMG-CoA) and therefore is a useful anti-hyperlipoproteinemic agent. It has proven to be a highly effective medicament for the treatment of disorders such as hyperlipidemia and hypercholesterolemia which are conditions that are known risk factors for arteriosclerosis and coronary heart disease. Atorvastatin is chemically R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrole-1-heptanoic acid and is marketed as its calcium salt trihydrate under the brand name Lipitor®, wherein a 2:1 molar ratio between atorvastatin and calcium ion exists. Herein the chemical name R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrole-1-heptanoic acid calcium salt is designated as atorvastatin calcium. In its dosage forms, atorvastatin calcium is currently ranked first in world-wide pharmaceutical sales.
The inhibition of the biosynthesis of cholesterol by atorvastatin was reported in U.S. Pat. No. 5,273,995. In this patent, it was indicated that the calcium salt form of the ring-opened lactone was most effective in terms of formulation.
Processes for the manufacture of atorvastatin and key synthetic intermediates have been described in various patents including U.S. Pat. Nos. 4,681,893, 5,003,080, 5,097,045, 5,103,024, 5,124,482, 5,149,837, 5,155,251, 5,216,174, 5,245,047, 5,248,793, 5,280,126, 5,397,792 and 5,342,952, U.S. Pat. No. 7,112,604 and US 2006/0199855. Typically, the final stages of the process involve the conversion of the precursor lactone [(2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, FIG. 2 (and referred to herein as atorvastatin lactone) into atorvastatin calcium, by base hydrolysis and exchange of cation to calcium.

Since atorvastatin calcium is a chiral, non-racemic molecule and because the drug is required in high purity for pharmaceutical purposes, it is important to have efficient and effective synthetic methods to remove undesired stereoisomeric impurities. Common techniques include the formation of a chiral salt often by using an expensive chiral base. Furthermore, this approach requires extra steps (salt formation, separation, free-basing). Other methods utilize stereoselective chemical transformation. However, these often require specialized reagents and highly-controlled reaction conditions.
F. Toda in Top. Curr. Chem. Vol. 140, pp. 43-69, 1987 provide examples of resolving chiral compounds by the formation of inclusion complexes. This approach has, to the knowledge of the inventors, been rarely used in organic chemistry and has never, to their knowledge, been used for the industrial preparation of pharmaceutical actives. This may be due to the fact that Toda's approach requires the restrictive combination that the substrate and chiral solvating agent must form a strong solvate and one that permits an effective separation.
With respect to atorvastatin calcium, a molecule which has two chiral centres, a cost-effective and high-yielding process to remove undesired stereoisomeric impurities would be advantageous.
Many processes have been proposed to prepare various polymorphic and pseudopolymorphic forms of atorvastatin calcium which all have varying degrees of stability, aqueous solubility, ease of preparation, hygroscopicity, bioavailability, etc. In particular, one of the most significant properties to improve would be to find a form that would offer improved stability which would result in a product having longer shelf-life. Atorvastatin calcium in an amorphous state, for example, is known to suffer from reduced stability with respect to, for example, photodecomposition (Tetrahedron, Vol. 49, pp. 1979-1984, 1993).
Solvated and hydrated forms of atorvastatin calcium include an acetone solvate (WO 2006/012499) as well as ethanol and butanol solvates (US 2005/0004206). Many hydrated forms of atorvastatin calcium are known and are taught, for instance in U.S. Pat. No. 5,969,156, U.S. Pat. No. 5,298,627, U.S. Pat. No. 6,992,194 and U.S. Pat. No. 6,605,729. As previously mentioned, the currently marketed form of atorvastatin calcium is a trihydrate form.
A proposed method to stabilize atorvastatin calcium is taught in US 2005/0106243 whereby free-flowing, pulverized adsorbates of atorvastatin calcium are disclosed. Preferably, the atorvastatin calcium is in a finely dispersed, amorphous form. These adsorbates are prepared by suspending atorvastatin calcium and an adsorber material in an organic solvent containing less than 10% water followed by evaporative solvent removal.
The use of propylene glycol as a solvating agent for selected pharmaceuticals is known, for instance Celecoxib (US 2006/0052432), Olanzapine (US 2006/0223794), Eplerenone (US 2005/0267302), Azithromycin (U.S. Pat. No. 6,977,243, U.S. Pat. No. 7,105,179), Conazoles (US 2004/0019211), Cefatrizine (JP 01290682), and Cephalosporin compounds (U.S. Pat. No. 4,091,213, U.S. Pat. No. 3,970,651, JP 105,813/75 and CA 1,101,840). A general patent application WO 2004/060347, which is related to the above Celecoxib and Olanzapine patent applications, suggests the general possibility of propylene glycol solvated forms of active pharmaceuticals and provides a lengthy list (>3000) including atorvastatin. However, details are only provided for only selected examples.
Given the difficulties associated with finding suitable processes to produce pharmaceutically pure and oxidatively stable forms of atorvastatin calcium, new and industrially acceptable solutions, which offer advantages relative to the prior art, were required.
It is therefore an object of this invention to provide new solvated forms of atorvastatin calcium and processes for their preparation.
Further and other objects of the invention will be realized by those skilled in the art from the following Summary of the Invention and Detailed Description of Preferred Embodiments of the Invention thereof.